Research ArticleClinical Studies
Open Access

High Expression of PKCζ and ALDH1A3 Is Associated With Poor Prognosis in Luminal B Breast Cancer

YUKA NAGASHIMA, KAZUNORI SASAKI, KANA NOHATA, RYOSUKE CHIWAKI, YUKI MAEMURA, TAKAHIRO KASAI, AYAKA OZAKI, SHOMA TAMORI, SHIGEO OHNO and KAZUNORI AKIMOTO
Anticancer Research October 2025, 45 (10) 4357-4372; DOI: https://doi.org/10.21873/anticanres.17785

Abstract

Background/Aim: The relationship between the protein kinase C zeta (PKCζ) and aldehyde dehydrogenase 1 family member A3 (ALDH1A3) expression levels and endocrine therapy susceptibility in luminal A and luminal B breast cancer subtypes is unclear. Therefore, the present study aimed to analyze this relationship in terms of disease-specific survival.

Materials and Methods: Open-source datasets with clinical and gene expression information (METABRIC, n=2509; and TCGA Pan-Cancer Atlas, n=1084) were downloaded and analyzed. Kaplan-Meier survival and Cox proportional hazard analyses were performed.

Results: The results indicated that high PKCζ and ALDH1A3 expression levels were associated with a poor prognosis in patients with luminal B type breast cancer treated with endocrine therapy, including aromatase inhibitors. These results suggest that high expression of PKCζ and ALDH1A3 contributes to reduced effectiveness of endocrine therapy in patients with luminal B breast cancer.

Conclusion: PKCζ may be involved in the progression of ALDH1A3-positive luminal B breast cancer. Furthermore, PKCζ and ALDH1A3 could serve as molecular targets and prognostic biomarkers for predicting the efficacy of endocrine therapy in patients with ALDH1A3 positive luminal B breast cancer.

Keywords:

Introduction

Breast cancer is the leading cause of death among women worldwide (1). Therefore, it is needed to clarify the characteristics of breast cancer progression and recurrence, as well as to develop effective treatments. Breast cancer is classified into several subtypes via immunohistochemical classification based on receptor expression [including luminal A, luminal B, human epidermal growth factor receptor type 2 (HER2) and triple negative breast cancer] and via classification based on gene expression patterns (including the PAM50 and claudin-low classifiers: normal-like, luminal A, luminal B, HER2-enriched, claudin-low and basal-like) (2-8). Both the luminal A and luminal B subtypes are estrogen receptor (ER)-positive and account for 70-80% of breast cancer cases (9). Furthermore, many luminal B tumors exhibit high expression of HER2 and Ki-67 (MKI67) (10-12). The standard of drug care for luminal A and luminal B breast cancer involves the administration of endocrine therapy, while luminal B breast cancer is also treated with HER2-targeted drugs. However, luminal B breast cancer has a poorer prognosis than luminal A breast cancer (10-17). Therefore, it is needed to identify biomarkers that further stratify luminal B breast cancer and to predict the effects of drug treatments.

Cancer stem cells (CSCs) are undifferentiated cancer cells that possess stem cell-like features such as self-renewal, multipotency and tumorigenicity (18, 19). Since CSCs are resistant to conventional antitumor treatments such as drug therapy and radiotherapy, the development of molecular-targeted therapies against CSCs is necessary to improve clinical outcomes for patients (18-21). Aldehyde dehydrogenase 1 (ALDH1) is a detoxifying enzyme that converts aldehydes to carboxylic acids and is known as a CSC marker (22). Specifically, the ALDH1 isoforms ALDH1A1 and ALDH1A3 are major CSC markers (23, 24). In endocrine therapy resistance, the Jagged-1 (JAG1)-NOTCH4-dependent ALDH1 activity promotes tamoxifen resistance in breast cancer cells (25). Tamoxifen directly binds to and activates ERα36, a truncated variant of the ER, which enhances stemness by upregulating ALDH1A1 expression and promotes the metastasis of ERα36-positive breast cancer cells (26). The expression of ALDH1A3 is correlated with tumor grade, metastasis and prognosis of patients with breast cancer (27-29), and ALDH1A3 significantly contributes to ALDH1 activity in breast cancer (28, 30). High ALDH1A3 expression is also associated with chemoresistance and radioresistance in several cancer types (23, 30, 31). However, the relationship between ALDH1A3 expression and the susceptibility to endocrine therapy in breast cancer remains unclear.

Atypical protein kinase C (aPKC) is a Ser/Thr kinase belonging to the PKC subfamily and is insensitive to Ca2+ and diacylglycerol/ phorbol esters (32-34). aPKC has two isoforms, PKCζ and PKCλ/℩ (32-34), and its activation depends on lipids such as PI(3,4,5)P3 or ceramide (35-38) and PB1-PB1 domain interaction with the PAR-6-CDC42/RAC complex (33, 39, 40). PKCζ regulates diverse biological functions such as cell polarity (33), inflammation (41) and apoptosis (42-44), and has important roles in cancer cell proliferation and invasion (45-47). Experimental studies using cell lines and animal models have reported that PKCζ is involved in endocrine resistance with tamoxifen treatment, chemoresistance with taxane, cisplatin and doxorubicin treatments and radioresistance in cancer cell lines (48-52). Furthermore, high PKCζ expression in patients with luminal B breast cancer treated with endocrine therapy, especially aromatase inhibitors, indicates a poor prognosis (53). However, the relationship between the PKCζ and ALDH1A3 expression levels and the efficacy of endocrine therapy in luminal B breast cancer remains unclear.

The aim of the present study was to examine the effect of the PKCζ and ALDH1A3 expression levels on endocrine therapy in breast cancer. The results indicated that PKCζhigh ALDH1A3high luminal B breast cancer treated with endocrine therapy, including aromatase inhibitor as endocrine therapy, is associated with a poor prognosis. These results suggest that high expression of PKCζ and ALDH1A3 contribute to reduced susceptibility to endocrine therapy in patients with luminal B breast cancer. Thus, PKCζ may be involved in the progression of ALDH1A3-positive luminal B breast cancer. Furthermore, PKCζ and ALDH1A3 could serve as molecular targets and prognostic biomarkers for predicting the efficacy of endocrine therapy in patients with ALDH1A3 positive luminal B breast cancer.

Materials and Methods

Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. The METABRIC dataset (n=2509) (54, 55) was downloaded from cBioPortal (56, 57) on March 29, 2022. The details of the data are shown in Figure 1 and also reported previously (53).

Figure 1.
Figure 1.

Overall workflow and design of the present study.

The Cancer Genome Atlas (TCGA) dataset. TCGA Pan-Cancer Atlas dataset (n=1084) (58) was downloaded from cBioPortal (56, 57) on April 1, 2025. The details of the data are shown in Figure 1 and also reported previously (53).

Prognostic analyses. Prognostic analyses of the disease-specific survival (DSS) data were performed as previously described (53, 59-61). Briefly, patients were divided into the high and low PKCζ and ALDH1A3 expression groups (Figure 1), and receiver operating characteristic curves were plotted using the DSS data and the Youden index was utilized as the optimal cut-off (Table I). For the Kaplan-Meier analysis, p-values were calculated using the Cochran-Mantel-Haenszel generalized log-rank test and multiplicity was adjusted using the Holm test as the post hoc test. In the multivariate Cox regression analysis, age at diagnosis was used as a confounding factor in Table II and Table III. In Table II, chemotherapy and radiation therapy were also included as additional confounding factors. Two-sided p<0.05 was considered to indicate a statistically significant difference.

View this table:
Table I.

Youden index calculated by receiver operating characteristic curve analysis of each group from the METABRIC and TCGA Pan-Cancer Atlas datasets.

View this table:
Table II.

DSS Multivariate Cox regression analyses according to PKCζ and ALDH1A3 expression in patients with different luminal subtypes of breast cancer treated with endocrine therapy in the METABRIC dataset.

View this table:
Table III.

DSS Multivariate Cox regression analyses according to PKCζ and ALDH1A3 expression in patients with different luminal subtypes of breast cancer treated with different endocrine therapy types in TCGA Pan-Cancer Atlas dataset.

Results

PKCζhigh ALDH1A3high indicates a poor DSS prognosis in patients with luminal B breast cancer treated with endocrine therapy in the METABRIC dataset. Our previous study demonstrated that endocrine therapy had low efficacy in patients with PKCζhigh luminal B breast cancer (53). However, the relationship between cancer stemness and high PKCζ expression in luminal B breast cancer is unclear. We also demonstrated that patients with luminal B breast cancer with high p62 (a PKCζ interacting molecule) and ALDH1A3 expression exhibited a poor prognosis (62). Therefore, to examine the prognosis of patients with higher PKCζ and ALDH1A3 expression levels in luminal B breast cancer treated with endocrine therapy, DSS Kaplan-Meier and multivariate Cox regression analyses were performed and compared with those of patients with luminal A breast cancer. The overall workflow of the present study is shown in Figure 1. The results demonstrated that patients with high expression of both PKCζ and ALDH1A3 in luminal A and luminal B breast cancer treated without endocrine therapy did not exhibit a poor prognosis (luminal A, p=0.113; luminal B, p=0.166; log-rank test). However, patients with PKCζhigh ALDH1A3high luminal B breast cancer treated with endocrine therapy exhibited a poor prognosis (p=0.015; log-rank test) (Figure 2). DSS multivariate Cox regression analysis also demonstrated that patients with PKCζhigh ALDH1A3high luminal B breast cancer treated with endocrine therapy had a poor prognosis [hazard ratio (HR)=3.15, 95% confidence interval (CI)=1.26-7.86, p=0.01], while patients with PKCζhigh ALDH1A3high luminal B breast cancer treated without endocrine therapy did not [HR=0.36, 95%CI=0.14-0.88, p=0.03] (Table II). These results suggest that PKCζ may contribute to reduced effectiveness of endocrine therapy in ALDH1A3-positive luminal B breast cancer.

Figure 2.
Figure 2.

DSS Kaplan-Meier analyses of the luminal breast cancer subtypes according to PKCζ and ALDH1A3 expression and endocrine therapy in the METABRIC dataset. (A-F) METABRIC data were downloaded from cBioPortal. (A) All patients with breast cancer, (B) patients with luminal A breast cancer and (C) patients with luminal B breast cancer who were treated without endocrine therapy. (D) All patients with breast cancer, (E) patients with luminal A breast cancer and (F) patients with luminal B breast cancer treated with endocrine therapy. Comparison of the PKCζhigh ALDH1A3high vs. PKCζhigh ALDH1A3low vs. PKCζlow ALDH1A3high vs. PKCζlow ALDH1A3low groups of patients. p-Values were calculated using the Cochran-Mantel-Haenszel generalized log-rank test. The adjusted p-values for the PKCζhigh ALDH1A3high group vs. the PKCζhigh ALDH1A3low, PKCζlow ALDH1A3high and PKCζlow ALDH1A3low groups were determined using the Holm method. METABRIC: Molecular Taxonomy of Breast Cancer International Consortium; DSS: disease-specific survival; PKCζ: protein kinase C zeta; ALDH1A3: aldehyde dehydrogenase 1 family member A3.

PKCζhigh ALDH1A3high indicates a poor DSS prognosis in patients with luminal A or luminal B breast cancer treated with aromatase inhibitors as endocrine therapy in TCGA dataset. To validate the above results from the METABRIC dataset analyses, another breast cancer cohort, TCGA Pan-Cancer Atlas (58), was analyzed; however, the average observation period in this dataset (DSS, 40.5 months) was shorter than that in the METABRIC dataset (DSS, 123.6 months). Thus, TCGA Pan-Cancer Atlas dataset was used to examine the effects of endocrine therapy on DSS in PKCζhigh ALDH1A3high luminal A or luminal B breast cancer using Kaplan-Meier and multivariate Cox regression analyses. As shown in Figure 3 and Table III, unlike the METABRIC dataset, PKCζhigh ALDH1A3high was not associated with a poor prognosis in either of the breast cancer subtypes treated with endocrine therapy (luminal A, p=0.066; luminal B, p=0.061; log-rank test). The difference between the results from the two patient cohorts may be due to the smaller number of patients, more censoring and a shorter observation period in TCGA Pan-Cancer Atlas dataset compared with the METABRIC dataset.

Figure 3.
Figure 3.

DSS Kaplan-Meier analyses of the luminal breast cancer subtypes according to PKCζ and ALDH1A3 expression and endocrine therapy in TCGA Pan-Cancer Atlas dataset. (A-F) TCGA Pan-Cancer Atlas data were downloaded from cBioPortal. (A) All patients with breast cancer, (B) patients with luminal A breast cancer and (C) patients with luminal B breast cancer who were treated without endocrine therapy. (D) All patients with breast cancer, (E) patients with luminal A breast cancer and (F) patients with luminal B breast cancer treated with endocrine therapy. Comparison of the PKCζhigh ALDH1A3high vs. PKCζhigh ALDH1A3low vs. PKCζlow ALDH1A3high vs. PKCζlow ALDH1A3low groups of patients. p-values were calculated using the Cochran-Mantel-Haenszel generalized log-rank test. The adjusted p-values for the PKCζhigh ALDH1A3high group vs. the PKCζhigh ALDH1A3low, PKCζlow ALDH1A3high and PKCζlow ALDH1A3low groups were determined using the Holm method. TCGA: The Cancer Genome Atlas; DSS: disease-specific survival; PKCζ: protein kinase C zeta; ALDH1A3: aldehyde dehydrogenase 1 family member A3.

TCGA dataset contains data on endocrine therapy drugs with two different modes of action, including the anti-estrogen drug, tamoxifen, and aromatase inhibitors administered to postmenopausal women such as anastrazole, letrozole and exemestane. As shown in Figure 4, patients with PKCζhigh ALDH1A3high luminal A or luminal B breast cancer treated with tamoxifen did not exhibit a poor prognosis (luminal A, p=0.201; luminal B, p=0.131; log-rank test). However, as in the METABRIC dataset, patients with PKCζhigh ALDH1A3high luminal B breast cancer treated with aromatase inhibitors exhibited a poor clinical outcome (p=0.003; log-rank test), although the number of PKCζhigh ALDH1A3high breast cancer cases treated with aromatase inhibitors was small (Figure 4). These results suggest that the reduced effectiveness of endocrine therapy in PKCζhigh ALDH1A3high luminal B breast cancer observed in the METABRIC dataset may be due to the reduced effect of aromatase inhibitors, as indicated by TCGA dataset results. Notably, unlike in the METABRIC dataset, patients with PKCζhigh ALDH1A3high luminal A breast cancer treated with aromatase inhibitors in TCGA dataset also exhibited a poor clinical outcome (p=0.029; log-rank test) (Figure 4). Thus, these results indicated that patients with PKCζhigh ALDH1A3high luminal A or luminal B breast cancer treated with aromatase inhibitors as endocrine therapy exhibited a poor clinical outcome.

Figure 4.
Figure 4.
Figure 4.

DSS Kaplan-Meier analyses of the luminal breast cancer subtypes according to PKCζ and ALDH1A3 expression and the endocrine therapy types in TCGA Pan-Cancer Atlas dataset. (A-L) TCGA Pan-Cancer Atlas data were downloaded from cBioPortal. (A) All patients with breast cancer, (B) patients with luminal A breast cancer and (C) patients with luminal B breast cancer who were treated without tamoxifen. (D) All patients with breast cancer, (E) patients with luminal A breast cancer and (F) patients with luminal B breast cancer who were treated with tamoxifen. (G) All patients with breast cancer, (H) patients with luminal A breast cancer and (I) patients with luminal B breast cancer who were treated without aromatase inhibitors. (J) All patients with breast cancer, (K) patients with luminal A breast cancer and (L) patients with luminal B breast cancer who were treated with aromatase inhibitors. Comparison of the PKCζhigh ALDH1A3high vs. PKCζhigh ALDH1A3low vs. PKCζlow ALDH1A3high vs. PKCζlow ALDH1A3low groups of patients. p-Values were calculated using the Cochran-Mantel-Haenszel generalized log-rank test. The adjusted p-values for the PKCζhigh ALDH1A3high group vs. the PKCζhigh ALDH1A3low, PKCζlow ALDH1A3high and PKCζlow ALDH1A3low groups were determined using the Holm method. TCGA: The Cancer Genome Atlas; DSS: disease-specific survival; PKCζ: protein kinase C zeta; ALDH1A3: aldehyde dehydrogenase 1 family member A3.

Discussion

In the present study, it was demonstrated that high expression of PKCζ and ALDH1A3 contributed to the reduced effectiveness of endocrine therapy (including aromatase inhibitor as endocrine therapy) in patients with luminal B breast cancer in the METABRIC and TCGA Pan-Cancer Atlas datasets. These results suggest that high expression of PKCζ and ALDH1A3 contributes to reduced susceptibility to endocrine therapy in patients with luminal B breast cancer and PKCζ may be involved in the progression of ALDH1A3-positive luminal B breast cancer. Our recent study demonstrated that patients with high CTNNBIP1 (an inhibitory regulator of the Wnt signaling pathway) and PKCζ expression in luminal B breast cancer treated with endocrine therapy exhibit a poor clinical outcome (53). How PKCζ and CTNNBIP1 are involved in the reduced efficacy of aromatase inhibitors in ALDH1A3-positive luminal B breast cancer remains an important future question. Additionally, the multidomain protein p62 interacts with PKCζ via PB1-PB1 domain interaction (47, 63-65). We recently reported that patients with luminal B breast cancer with high p62 and ALDH1A3 expressions exhibited a poor prognosis (62, 66) and that p62 deficiency in ALDH1high luminal B cell lines suppresses tumor-sphere formation (62, 66). Thus, the interaction with p62 may be involved in the PKCζ-mediated reduced effectiveness of endocrine therapy and aromatase inhibitors in ALDH1A3-positive luminal B breast cancer. Furthermore, the JAG1-NOTCH4-dependent ALDH1 activity promotes tamoxifen resistance in breast cancer cells (25). Tamoxifen directly binds to and activates ERα36, a truncated variant of the ER, to enhance stemness by upregulating ALDH1A1 expression and promotes the metastasis of ERα36-positive breast cancer cells (26). Based on these findings and the fact that the site of action of tamoxifen and aromatase inhibitors is different, it is possible that different mechanisms are involved in the resistance to tamoxifen and aromatase inhibitors in ALDH1A1- and ALDH1A3-positive CSCs. In the future, the detailed mechanism linking PKCζ to aromatase inhibitor resistance in ALDH1A3-positive CSCs should be elucidated. The luminal B breast cancer subtype often exhibits HER2 positivity (10-12). TCGA dataset also contains information on HER2-targeted therapy. Therefore, we examined the effect of high PKCζ and ALDH1A3 expression on HER2-targeted therapy in luminal B breast cancer, but the prognosis analysis was not possible as no deaths occurred among the patients who received this therapy in the dataset. Thus, the effect of HER2-targeted therapy in PKCζhigh ALDH1A3high luminal B breast cancer remains to be determined.

In TCGA dataset analyzed in the present study, unlike in the METABRIC dataset, patients with PKCζhigh ALDH1A3high luminal A breast cancer treated with endocrine therapy exhibited a poor prognostic tendency (Figure 3) and patients with PKCζhighALDH1A3high luminal A breast cancer treated with aromatase inhibitors exhibited a poor prognosis (Figure 4). Therefore, the effects of aromatase inhibitors in PKCζhigh ALDH1A3high luminal A breast cancer require further detailed cohort studies.

PKCλ, another isoform of the aPKC family, is involved in the resistance to chemotherapy agents such as cisplatin and gemcitabine in laryngeal squamous cell carcinoma and gallbladder cancer in cell experiments and human sample analyses (67, 68). PKCλ regulates the ALDH1A3-positive CSC properties such as tumor formation, low reactive oxygen species levels, cell survival, cell motility and asymmetric cell division (69-71). Further analysis is needed to determine any similarities in the functions of PKCζ and PKCλ in treatment resistance in breast cancer.

Conclusion

In the present study, high expression of PKCζ and ALDH1A3 contributes to reduced effectiveness of endocrine therapy in patients with luminal B breast cancer and PKCζ may be involved in the progression of ALDH1A3-positive luminal B breast cancer. Therefore, PKCζ and ALDH1A3 could serve as molecular targets and prognostic biomarkers for predicting the efficacy of endocrine therapy in ALDH1A3-positive luminal B breast cancer.

Footnotes

  • Authors’ Contributions

    Conceptualization: YN, KS, and KA; formal analysis: YN, KS, KN, and RC; Funding Acquisition: YN, KS, ST, SO, and KA; Investigation: YN, KS, KN, RC, and KA; Methodology: KS, KN, AO, and KA; Project Administration: KA; Supervision: KA; Validation: KS, RC, YM, TK, and ST; Visualization: YN and KN; Writing – Original Draft Preparation: YN, KN, and KA; Writing – Review & Editing: YN, KS, KN, RC, YM, TK, AO, ST, SO, and KA.

  • Conflicts of Interest

    The Authors declare that they have no competing interests in relation to this study.

  • Funding

    The present study was supported by Tokyo University of Science Grant for President’s Research Promotion, JST Moonshot R&D (grant no. JPMJPS2022-21), Grant-in-Aid for Scientific Research (C) (grant no. 20K08936, 24K12517), Grant-in-Aid for Early-Career Scientists (grant no. 23K14352), JST SPRING (grant no. JPMJSP2151), Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan, Grant from Institute for Environmental & Gender-specific Medicine, Juntendo University.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received June 28, 2025.
  • Revision received July 18, 2025.
  • Accepted July 21, 2025.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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High Expression of PKCζ and ALDH1A3 Is Associated With Poor Prognosis in Luminal B Breast Cancer
YUKA NAGASHIMA, KAZUNORI SASAKI, KANA NOHATA, RYOSUKE CHIWAKI, YUKI MAEMURA, TAKAHIRO KASAI, AYAKA OZAKI, SHOMA TAMORI, SHIGEO OHNO, KAZUNORI AKIMOTO
Anticancer Research Oct 2025, 45 (10) 4357-4372; DOI: 10.21873/anticanres.17785
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